Critique 260: Two studies on the Mediterranean alcohol-drinking pattern and its association with hypertension and all cause mortality in the Seguimiento Universidad de Navarra” (SUN) cohort 22 January 2023
Mediterranean alcohol-drinking patterns and all-cause mortality in women more than 55 years old and men more than 50 years old in the “Seguimiento Universidad de Navarra” (SUN) cohort
Barbería-Latasa M, Bes-Rastrollo M, Pérez-Araluce R, Martínez-González MÁ, Gea A. Nutrients. 2022 Dec 14;14(24):5310. doi.org/10.3390/nu14245310. PMID: 36558468; PMCID: PMC9788476.
Background: Most of the available epidemiological evidence on alcohol and chronic disease agrees on recommending alcohol abstention to young people, but some controversy exists about the most appropriate recommendation for alcohol abstention for people of older ages. A growing body of evidence suggests that the pattern of alcohol consumption is likely to be a strong effect modifier. The Mediterranean Alcohol Drinking Pattern (MADP) represents a score integrating several dimensions of drinking patterns (moderation, preference for red wine, drinking with meals, and avoiding binge drinking). Our aim was to clarify this issue and provide more precise recommendations on alcohol consumption.
Methods: We prospectively followed-up 2226 participants (men older than 50 years and women older than 55 years at baseline) in the Seguimiento Universidad de Navarra (SUN) cohort. We classified participants into three categories of adherence to the MADP score (low, moderate, and high), and we added a fourth category for abstainers. Cox regression models estimated multivariable-adjusted hazard ratios (HR) of all-cause death and 95% confidence intervals (CI) using low MADP adherence as the reference category.
Results: The strongest reduction in risk of mortality was observed for those with high adherence to the MADP, with an HR of 0.54 (95% CI: 0.37–0.80). The moderate adherence group (HR = 0.65, 95% CI: 0.44–0.96) and the abstention group (HR = 0.60, 95% CI: 0.36–0.98) also exhibited lower risks of mortality than the low MADP adherence group.
Conclusions: Based on the available evidence, a public health message can be provided to people older than 50 years as follows: among those who drink alcohol, high adherence to the MADP score could substantially reduce their risk of all-cause mortality.
Mediterranean alcohol-drinking pattern and arterial hypertension in the “Seguimiento Universidad de Navarra” (SUN) prospective cohort study
Hernández-Hernández A, Oliver D, Martínez-González MA, Ruiz-Canela M, Eguaras S, Toledo E, de la Rosa PA, Bes-Rastrollo M, Gea A. Nutrients. 2023; 15(2):307. doi.org/10.3390/nu15020307
Alcohol drinking patterns may determine the risk of hypertension and may also modify the detrimental effect of high alcohol intake. We prospectively evaluated the effect of the Mediterranean alcohol-drinking pattern and its interaction with the amount of alcohol consumed on the incidence of arterial hypertension.
Methods: In the “Seguimiento Universidad de Navarra” (SUN) cohort, we followed-up 13,805 participants, all of them initially free of hypertension, during a maximum period of 16 years. Information about diet, chronic diseases, lifestyle and newly diagnosed hypertension was collected using validated questionnaires. We used a 7-item score (0 to 9 points) that jointly considered moderate alcohol consumption, distributed over the week, with meals, and a preference for red wine and avoidance of binge-drinking. During 142,404 person-years of follow-up, 1443 incident cases of hypertension were identified.
Results: Low adherence (score < 2) to the Mediterranean alcohol-drinking pattern was significantly associated with a higher incidence of hypertension (multivariable-adjusted hazard ratio 1.81, 95% confidence interval 1.09–2.99) as compared to the high-adherence (score > 7) category. Among alcohol consumers, a high adherence to the MADP is associated with a lower incidence of hypertension.
Conclusions: Compared with abstinence, a high adherence did not seem to differ regarding its effect on hypertension risk.
These are two papers from the SUN study cohort concerning alcohol and its potential beneficial effects when part of a Mediterranean diet and lifestyle. One is specifically related to arterial hypertension in a larger cohort of all-aged adults (13,805 participants); it is considered the most widespread among all modifiable risk factors for atherosclerosis development which is duly considered the main cause of cardiovascular disease (CVD), itself the leading global cause of premature mortality. The other paper is related to all-cause mortality in a smaller cohort of older adults (2226 participants), where the risk of CVD begins to increase (Rodgers et al. 2019).
These two papers, however, are on two very different diseases. Most importantly, arterial hypertension and CVD, (or at least as classical atherosclerosis), have very different aetiologies. Alcohol/wine/beer protects against atherosclerosis but less against hypertension. In fact, hypertension may increase at higher consumption levels. For example, Beulens et al. (2007) investigated the protective effects of moderate drinking in hypertensives and found that those were protected because their incidence for myocardial infarction decreased, but not risks for all-cause mortality or mortality from CVD.
Forum member Stockley noted that: “Gronbaek et al. (1998) had previously reported identical J-shaped relationships between all-cause mortality and alcohol consumption for middle-aged and older participants. Thun et al. (1997) also noted decreased risk of all-cause mortality with usual consumption for both middle-aged (30–59 years) and older (60–79 years) men and women. Studies have not suggested a decreased cardioprotective effect of usual alcohol consumption as a function of age but rather a preservation of its beneficial effects, at least in men and at the generally moderate amounts of alcohol consumption (Snow et al. 2009).
The relationship between alcohol consumption and the risk of all-cause mortality does appear to be age dependent (Rehm and Sempos 1995). A cardioprotective effect is first observed, however, when risk factors for CVD begin to influence medium and long-term health, that is, at approximately age 40 years for men and approximately age 50 years for women (Tolstrup and Gronbeck 2007, Hvidtfeldt et al. 2010). Accordingly, in women, onset of cardioprotection depends on the age of onset of menopause and use of hormone replacement therapy (Stampfer et al. 1988, Klatsky et al. 1992, Holman et al. 1996, Thun et al. 1997, Di Castelnuovo et al. 2006, Klatsky and Udaltosova 2007, Snow et al. 2009). Furthermore, initiation of moderate alcohol consumption at ages 45-64 years has also been associated with an up to 40% reduction in CVD risk compared to both abstinence and light consumption after approximately four years which was maintained even when other CVD risk factors were considered (Sesso et al. 2000, Friesema et al. 2007, King et al. 2008). Cardioprotection, for example, generally continues past 65 and 75 years of age (Simons et al. 2000, Perissinotto et al. 2010, McCaul et al. 2010, Simons et al. 2014). Simons et al. (2014) in a population of 2805 non-institutionalised participants aged 60 years and older, observed accordingly that at 20 years of follow-up, there is significant protection from CVD for moderate alcohol consumers compared to both abstainers and heavy consumers. In addition, men and women consuming any alcohol survived 12 months longer than their abstinent peers. This relationship did not appear to be impacted or mediated by the CVD risk factors of diabetes, hypertension, obesity or the ratio of LDL to HDL cholesterol.”
Forum member Stockley also noted that “the SUN (Seguimiento Universidad De Navarra) study represents one of the main cohorts in the European Mediterranean area aiming to explore the association between dietary factors and non-communicable diseases. The SUN study had previously observed (Carlos et al. 2018) that better adherence to the Mediterranean diet which includes moderate alcohol consumption with meals was significantly associated with a lower risk of all-cause mortality (Alvarez-Alverez et al. 2018), cardiovascular disease (CVD) incidence and mortality (Martínez-González et al. 2011), and, more recently, a composite outcome including all-cause mortality, CVD and type-2 diabetes (Domínguez et al. 2014). Also as previously observed in the SUN study, these results may be explained by several findings reported for cardiovascular risk factors, including a decrease in mean systolic and diastolic blood pressure (Núñez-Córdoba et al. 2009), reduction in the risk of developing type-2 diabetes (Eguaras et al. 2017) and reduction in weight gain over the approximate 20-year follow up period (Beunza et al. 2010). The present analysis provides an additional explanation of a reduction in arterial hypertension for these results as well as supporting a previous observation of a lower risk of all-cause mortality (Alvarez-Alvarez et al. 2018).
Wine preference was associated with 75% of alcohol consumed as wine where moderate total alcohol consumption ranged from 5 to 25 g/day for women and 10-50 g/day for men; this equates to 0.5 to 2.5 10 g drinks per day for women and 1 to 5 for men. That these amounts are related to a significant reduction in all-cause mortality for both ageing women and men shows that the SUN study results are consistent with the results of earlier meta-analyses of cohort studies showing a J-shaped relationship between mortality and alcohol consumption with sex-specific thresholds. For example, a significant mortality risk reduction up to 20 g/day for men and up to 10 g/day for women by English et al. (1995) and up to 40 g/day for men and up to 20 g/day for women by Di Castelnuovo et al. (2006).
Klatsky and Udaltsova (2007) also showed a J-shaped relationship between alcohol consumption per se and all-cause mortality risk suggesting an increased risk for individuals consuming more than three (14 g) drinks per day and a reduced risk at three or less drinks (14 g) per day, almost always due to a reduced risk of death from CVD; former alcohol consumers were observed to be at increased risk of death from non-CVD and occasional consumers were observed to have a risk similar to lifelong abstainers. Fuller (2011) subsequently showed that the significant majority of prospective studies indicate that moderate alcohol consumers have a lower all-cause mortality and risk of CVD, lending credence to the argument that the inverse association between moderate alcohol consumption and mortality is causal. Furthermore, the supplementary data to Wood et al. (2018) clearly show that the risk of all cardiovascular events is lower for light/moderate consumers, and in particular, there was a J-shaped relationship between the risk of alcohol consumption and all cardiovascular events; the greatest reduction in the risk was at 100-200 g/week of alcohol, i.e. 1-2 10 standard drinks/day or 10-20 g alcohol/day. Also, never-drinkers even had a greater risk of all cardiovascular events than consumers who drank >600 g/week of alcohol, that is, more than 60 standard drinks/week.”
Comments by specific Forum members
Forum member Finkel observed: “The two Spanish papers solidify what many of us have long believed, based on data published over and over again: a healthy life style and moderate alcohol consumption, particularly of red wine, enhances health. Their appearance is timely, serving to give proper perspective to the inexhaustible voices of prohibition, whose crusade is once again exhibited prominently in the New York Times, as informed by the too-familiar Tim Naimi.”
Forum member Hendriks commented: “The first paper by Barberiá-Latasa et al. is an interesting paper looking into the best drinking pattern. It further extends our knowledge on the relation between moderate drinking and all-cause mortality. Although the abstract introduction initially focuses on what to recommend to young adults, the general introduction does not further elaborate on that issue. Possibly because the relatively small part of the total initial population study focuses on people aged 50 and older.
Also, the scoring system is really targeted towards moderate wine drinking: moderate drinking 2 points, preferring wine drinking 1 point, selecting wine over other beverages 1 point, lower spirits consumption 1 point, etcetera. So, the Mediterranean alcohol drinking pattern is not only looking at an alcohol drinking pattern, but focuses preferably on wine drinking. The title may as well have been Mediterranean wine drinking pattern and all-cause mortality. Remarkably, death rate was quite high for a population with a mean age of almost 60 and an average follow-up of 14 years; almost 300 persons died (men mainly) of the total of 2226 whereas already 776 persons with underlying disease were excluded.
The second paper by Hernández-Hernández et al. is also an interesting paper from the same cohort relating lifestyle and hypertension incidence. The paper is interesting since alcohol consumption has been associated with hypertension, but is also affected by various other lifestyle factors. This paper also focuses on alcohol drinking and more specifically on wine drinking. The paper nicely shows that hypertension is positively associated with alcohol drinking but that the way of drinking (wine mainly, spread out over the week, avoiding binge drinking) also mediates the association, namely when drinking ‘the Mediterranean way’ alcohol consumption level is not associated with hypertension up to a high level of alcohol consumption.
The two papers are directly related since they study the population of the same area. However, the outcomes are not directly related: the two study populations used from the same area differ: mortality is studied in an older cohort, whereas hypertension is studied in a relatively young cohort. Also the outcomes differ quite a bit: mortality in the first study is mainly caused by cancers whereas hypertension is an important risk factor leading into coronary heart disease. Both papers, however, point in the same direction, namely the Mediterranean lifestyle may be considered as a healthy lifestyle including the regular and moderate consumption of wine.”
Forum member Ellison commented: “The first paper by Barberiá-Latasa et al. reviewed from the SUN study related the pattern of drinking alcohol to mortality among older subjects (> 50 years for men and >55 years for women). The investigators constructed a Mediterranean Drinking Pattern score based on regularity of consumption of moderate amounts, with food, more likely to be red wine, less likely to be spirits, and the lack of binge drinking. The results may be somewhat limited by a relatively small number of non-drinkers (n=35, for whom the degree of compliance with the Mediterranean Diet was not shown), and the small number of drinkers who had low compliance with the Mediterranean Drinking Pattern (n=35), with the latter chosen as the reference group. Nevertheless, the data clearly show a high degree of protection against risk of total mortality over an average follow-up time of 14 years for drinkers who followed the Mediterranean drinking pattern. Specifically, subjects with higher scores for the Mediterranean Drinking Pattern had significantly lower risk of mortality than drinkers who were less likely to consume alcohol in such a pattern. Further, when the investigators conducted trend tests for the score among drinkers, they observed a significant inverse linear trend (p = 0.003) for mortality risk. The benefit of the Mediterranean pattern of drinking was marked (in the range of a 50% reduction in mortality risk!) and did not appear to relate to the total amount of alcohol consumed. The potential effects of the Mediterranean diet itself were not tested.
Forum member Ellison went on to comment that “the second paper by Hernández-Hernández et al. relates the pattern of drinking to the risk of an initial diagnosis of hypertension. Again, subjects who followed common-sense guidelines for drinking (consuming alcohol regularly and moderately, with food, more likely to be red wine, no binge drinking, etc., giving them a higher drinking score) were apparently protected from developing hypertension when compared with subjects with a lower drinking score. In fact, the risk of hypertension for subjects with a high score was not increased at all for those consuming no more than 20 g/day of alcohol.
A weakness of this study is that the number of subjects in the low-adherence group was much smaller (n=156) compared with the other groups, yet it served as the referent category in the analyses. Further the low-adherence group was more likely to be younger, male, binged more, smoked more, consumed more alcohol and sugar-sweetened beverages, reported more recent weight gain, and had other unhealthy characteristics. While the investigators used multi-variable analyses that attempted to adjust for these factors, residual confounding is always a problem. Thus, it will be important that further studies with a larger number of subjects in the referent group confirm the observed relations shown in this study. According to their results, however, it seems clear that a drinking pattern of regular, moderate, wine consumption with food does not increase the risk of hypertension, an important message for the health of the population.
Forum member De Gaetano commented: “The two papers are both interesting in view of the use of a score of a “Mediterranean drinking way” instead of the traditional dose-effect relationship. It is important to underline that alcohol and especially wine consumption is not equivalent to consumption of a drug and requires, to be fully appreciated, those (possibly even other additional) elements included in the new score. Interesting is also the failure, by this new score, to show any harmful effect of wine on cancer. A limitation of both studies is the relatively small number of events in some groups of drinkers and abstainers. Usually, one includes among abstainers only those long-life, excluding formers drinkers. Apparently, this distinction has not been done. The recent Lancet paper by the GBD 2020 Alcohol Collaborators (2022) introduced the interesting measure of alcohol dose at which the risk is the same as that of abstainers. This data has not been measured in the SUN studies. In conclusion, both studies strongly support the suggestion to measure wine/alcohol effects on health and disease, by extending the simple dose-effect relationship”.
Forum member Skovenborg remarked: “When considering external validity in the second paper by Hernández-Hernández et al., the SUN cohort are university graduates and highly educated which undermines the external validity regarding the general population. On the other hand, it precludes the discussion of socio-economic status and education as possible confounders.
Looking at the exclusion of participants with SBP > 130 mmHg and DBP > 80 mmHg, the cut-off blood pressure values seem to be rather low and would normally be 140/90. Further, looking at self-reported diagnosis of hypertension: according to the validation study the sensitivity was low overall agreement was not very high. Furthermore their “gold standard” for validation: two isolated BP measurements has limited validity for being the correct blood pressure. Some misclassification must be expected as a trade-off between precision and sample size.
Concerning self-reported alcohol consumption, the intake of alcohol in the three categories of MADP adherence were rather low for a Mediterranean population; 14,8 g, 7,9 g and 8,3 g per day for low, moderate and high adherence. In comparison the study by Trevisan et al. (1987), had the following categories of drinkers: Light drinkers: ≤ 193 ml ethanol/week; light-moderate drinkers: 194-386 ml ethanol/week; moderate drinkers 387-483 ml ethanol/week; heavy drinkers 484-800 ml/week; very heavy drinkers ≥ 800 ml ethanol/week. Accordingly, a moderate intake of alcohol in this population would be 44-55 g alcohol/day = 4-5 drinks per day. I wonder whether we are looking at underreporting by the SUN cohort and a realistic self-reported intake of alcohol by an Italian wine-drinking population with no intention of under-reporting.
In addition, adherence to at Mediterranean diet (0-8) was about four for the three categories of MADP score groups which is actually not that high, so a very healthy diet does not seem to be a confounding factor. Looking then at MADP adherence, with a high MADP adherence score you may drink up to about 30 grams of alcohol per day before your risk of hypertension would increase in comparison with abstainers. This is the important message of the study and good news for all sensible drinkers of wine (or beer with meals).”
Forum member Skovenborg continued that the first paper by Barbería-Latasa et al., “is a very different paper than the hypertension study with an older age group and the ideal endpoint, all-cause mortality, that leaves no room for end point misclassification. Usually when you discuss the benefits of moderate alcohol consumption, you focus on reduced risk of CV disease and mortality, however, in this study (where the mean age of death was 76 years) only 1 in 5 participants died of CVD and almost 1 in 2 died of cancer. So, the first hypothesis might be, that a moderate, regular alcohol consumption with meals helped these people to survive (thanks to not dying of myocardial infarction in a young age) to an age where many people die of cancer instead of CVD. There were very few abstainers; half of the abstainers were women and half were non-smokers and they had a fair amount of physical activity. These people are not prone to an early death in general and not prone to death of cancer in particular, so the abstainers did very well in this study. The next hypothesis would be that with a healthy lifestyle you do not necessarily have to drink wine. We knew that already from several studies of abstainer groups like the Seventh Day Adventists. So what we have here is actually a study of cancer deaths, and what the results of the study tell us is that the “low adherence” group with a high intake of alcohol, probably a substantial amount of binge drinking, many smokers and many metabolic conditions, a low score on the Mediterranean diet and the lowest score on physical activity is “a basket of deplorables” (as the public health officers would call them) and with these people as reference group, everyone else in the study unsurprisingly do better – and there is really no significant difference between the levels of how much they do better.
The “Low adherence” men (93.5% were men) are what the different cancer societies have in mind when they proclaim that “regarding cancer no alcohol is the best choice”. The very important message of this study is that the SUN study results prove that message to be wrong. With a high (and even a moderate) adherence to the Mediterranean Alcohol drinking pattern it is possible to enjoy 2 glasses of wine with your meal most days of the week with no added all-cause mortality and even with no added cancer mortality according to the highly significant results of the sensitivity analysis of high adherence to MADP vs. low adherence with only cancer deaths included: 0.46 (0.26 – 0.81). Let’s drink to that in MADP style.”
Forum member Mattivi wrote: “The work by María Barbería-Latasa et al. discussing the relationship between all causes of mortality and MADP should reasonably make explicit that the differences observed are related to the preferential consumption of RED wine. In fact, the most differentiated class (MADP=8-9) seems to consist predominantly of red wine consumers.
The mode of consumption, at meals and fractionated throughout the day, and avoiding the concentration of wine (or other alcoholic drinks) consumption on a single occasion, is important both for the metabolism of ethanol, but no less so for the metabolism of polyphenols. All polyphenols are present in concentrations above 2 g/L in red wines. With the frequency of consumption considered in this study, the amount of ingested polyphenols from red wine is observed to be a very significant contributor to the total dietary intake. In particular, circulating metabolites for many classes of polyphenols, and in particular those deriving from the tannins (gamma valerolactones and valeric acids), reach very high concentrations and can persist for very long periods of time (Di Pede et al. 2022). In other words, the consumption pattern that corresponds to high adherence to MADP is likely to ensure increased circulating levels of polyphenol metabolites for a large part of the day. It is therefore likely that the observed results are not entirely attributable to alcohol.
This is a far from marginal aspect at a time when the international trend is towards a drastic decrease in RED wine consumption and an increased preference for white and sparkling wines.”
Forum members agreed with the conclusions of the authors that “Moderate red wine consumption at meals which is spread throughout the week, avoiding binge drinking, reduces the risk of all-cause mortality by 48%. These results are consistent with individual studies of each separate aspect of the pattern and with studies of a priori patterns.” Further, this paper strongly suggests that assessments of the relation of alcohol consumption to health should focus on the pattern of drinking, not just the total amount consumed.
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Comments on this paper were provided by the International Scientific Forum on Alcohol Research and specifically by the following members:
Creina Stockley, PhD, MSc Clinical Pharmacology, MBA; Principal, Stockley Health and Regulatory Solutions; Adjunct Senior Lecturer, The University of Adelaide, Adelaide, Australia
Henk Hendriks, PhD, Senior Researcher, Centre for Earth, Environmental and Life Sciences, Zeist, Netherlands
Harvey Finkel, MD, Hematology/Oncology, Retired (Formerly, Clinical Professor of Medicine, Boston University Medical Center, Boston, MA, USA)
R. Curtis Ellison, MD, Professor of Medicine, Emeritus; Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA
Giovanni de Gaetano, MD, PhD, in conjunction with his colleague, Augusto Di Castelnuovo, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo NEUROMED, Pozzilli, Italy
Erik Skovenborg, MD, specialized in family medicine, member of the Scandinavian Medical Alcohol Board, Aarhus, Denmark
Andrew L. Waterhouse, PhD, Department of Viticulture and Enology, University of California, Davis.